Delta-9-Tetrahydrocannabinol (also known as THC, Dronabinol and D9THC) is a naturally occurring compound and is the primary active ingredient in the controlled substance marijuana. Marijuana refers to the dried flowers and leaves of Cannabis Sativa, the hemp plant. These parts of the plant contain several compounds called cannabinoids (including Dronabinol), that may help patients with certain disease conditions. Dronabinol has been approved by the Food and Drug Administration (FDA) for the control of nausea and vomiting associated with chemotherapy and, more recently, for appetite stimulation of AIDS patients suffering from wasting syndrome. Synthetic dronabinol has been utilized as a pharmaceutically active ingredient, and cannabis-based medicines using botanical sources of cannibis rather than synthetic THC are also known in the art.
Currently, dronabinol is commercially available in the U.S. as a solution in a soft gelatin capsule under the tradename Marinol® from Unimed Pharmaceuticals, Inc., which is orally administered. Upon oral administration, the gelatin dissolves, releasing the drug. The dronabinol dissolved in sesame oil, is then absorbed during its passage through the gastrointestinal tract. Marinol is indicated for the treatment of: 1) anorexia associated with weight loss in patients with AIDS and 2) nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Marinol capsules are sold in 2.5 mg, 5 mg, or 10 mg dosages and formulated with the following inactive ingredients: sesame oil, gelatin, glycerin, (glycerol), methylparaben, propylparaben, and titanium dioxide. The Marinol soft gelatin capsule form of dronabinol is highly unstable at room temperature, and it is recommended that the product be stored at refrigerated (2-8° C.) or cool (8-15° C.) conditions (Marinol package label, Physicians Desk Reference®, ed. 2003). Additionally, Marinol should be packaged in a well-closed container and stored in a cool environment between 8° and 15° C. (46° and 59° F.). At the present time, dronabinol is the only approved cannabinoid drug commercially available.
Other formulations containing dronabinol appear in the art. In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of dronabinol. Olsen, J. L., Lodge, J. W., Shapiro, B. J. and Tashkin, D. P. (1976) An inhalation aerosol of D9THC. J. Pharmacy and Pharmacol. 28:86. However, dronabinol is known to deteriorate during storage, and the stability of the dronabinol in this formulation is suspect. In addition, the ethanol content in this formulation was so high (about 23%) that an aerosol was created with droplets too large to be effectively inhaled. See, Dalby, R. N. and Byron, P. R. (1988) Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions. Pharm. Res. 5:36-39. The dronabinol CFC formulations were tested for use in treating asthma but were shown to be only moderately effective. See, Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L. and Lidgek, J. W. (1977) Bronchial effects of aerosolized D9THC in healthy and asthmatic subjects. Amer. Rev. of Resp. Disease. 115:57-65; Williams, S. J., Hartley, J. P. R. and Graham, J. D. P. (1976) Bronchodilator effect of D9THC administered by aerosol to asthmatic patients. Thorax. 31:720-723. Moreover, CFC propellants have since been banned so that such a formulation is now useless.
U.S. Pat. No. 6,509,005 describes an aerosol-dispensable pharmaceutical formulation comprising a hydrofluoroalkane propellant, (for example, HFA 227 or HFA 134a) and dronabinol (D9THC), which formulation is said to be stable. The propellant is present in the range of approximately 78 to 100% by weight, and more particularly the propellant is present in the range of approximately 85 to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the dronabinol in the propellant but is stated that it is not required. If a solvent is used, preferably less than 20% by weight will be required, and most preferably less than 15% by weight will be required. The pharmaceutically effective concentration of dronabinol is preferably in the range of 0.05 to 10% by weight.
U.S. Pat. No. 6,747,058 and U.S. Patent Application Publication No. 2004/0162336 describe an aerosolizable formulation for delivery of delta-9-tetrahydrocannabinol in a semi-aqueous solvent, such as 35:10:55 alcohol:water:propylene glycol (v/v), which is said to produce a stable clear solution near the solubility point of the drug.
U.S. Pat. No. 6,383,513 describes a composition for nasal delivery comprising a cannabinoid in a biphasic delivery system, wherein the biphasic delivery system is an oil-in-water emulsion.
U.S. Patent Application Publication No. 2003/0229027 describes a method of preparing a pharmaceutical composition comprising a natural cannabinoid compound such as delta-9-tetrahydrocannabinol which is said to be stabilized which comprises such a compound and a glass of a sugar, a sugar alcohol, a mixture of sugars or a mixture of sugars alcohols. The natural cannabinoid compound is dissolved in an organic solvent that is soluble in water and the sugar, sugar alcohol, mixture of sugars or mixture of sugar alcohols is dissolved in water; the dissolved cannabinoid compound and the dissolved sugar(s) are mixed; and the mixture is then dried by freeze drying, spray drying, vacuum drying, or super critical drying.
U.S. Pat. Nos. 5,508,037 and 5,389,375 describe suppository formulations prepared by admixing a therapeutically effective amount of at least one dronabinol prodrug ester derivative with a suppository base which is said to provide long term stability to the suppository formulation.
Dronabinol has been used as an antiemetic to relieve nausea and vomiting in patients receiving cancer chemotherapy. Additionally, U.S. Pat. No. 6,703,418 describes a method of treating a patient with symptomatic HIV infection to stimulate weight gain in the patient, which comprises administering to the patient a pharmaceutical composition comprising dronabinol in an amount sufficient to cause an increase in weight of the patient.
Despite all of the work outlined above and elsewhere, to date a room temperature stable oral dosage form of a cannabinoid such as dronabinol in a capsule has not been achieved.